Glycopeptide antibiotics liquid formulations and methods and uses thereof

ABSTRACT

The invention relates to formulations and compositions comprising one or more glycopeptide antibodies or a pharmaceutically acceptable salt thereof for parenteral administration. In particular, stable liquid formulations and compositions comprising vancomycin or a pharmaceutically acceptable salt thereof, N-acetyl-methionine and one or more pharmaceutically acceptable excipients. The invention also relates to a process of preparing such compositions and methods and uses thereof.

RELATED APPLICATIONS

This application claims the benefit of and priority in and to U.S.Provisional Application No. 63/107,919, filed Oct. 30, 2020, which ishereby incorporated by reference herein in its entirety.

FIELD

Disclosed herein are liquid formulations comprising one or moreglycopeptide antibiotics or a pharmaceutically acceptable salt thereoffor parenteral administration. In particular, this disclosure relates toliquid formulations comprising vancomycin or a pharmaceuticallyacceptable salt thereof, N-acetyl-methionine and one or morepharmaceutically acceptable excipients. This disclosure also relates toa process of preparing such compositions, methods and uses thereof.

BACKGROUND

The following includes information that may be useful in understandingthe invention. It is not an admission that any of the informationspecifically or implicitly referenced herein is prior art, or essential,to the described or claimed invention. All references, including, butnot limited to, patents, patent applications, non-patent references, andproducts, mentioned herein and their respective disclosures are herebyincorporated by reference herein in their entirety.

Glycopeptide antibiotics are a class of naturally occurring orsemi-synthetic antimicrobial agents which act by inhibition of bacterialcell wall biosynthesis and/or membrane integrity. The glycopeptideantibiotics, such as vancomycin, teicoplanin, oritavancin, dalbavanc inand telavancin, have potent activity against a broad range ofGram-positive organisms, including staphylococci (includingmethicillin-resistant Staphylococcus aureus), Streptococcus spp. andEnterococcus spp. Among these glycoside antibiotics, vancomycin is mostwidely used with strong bactericidal activity against many Gram-positivebacteria, and is useful for treatment of resistant and/or severeinfections caused by susceptive strains of methicillin-resistant(beta-lactam-resistant) staphylococci.

Vancomycin is a tricyclic glycopeptide antibiotic derived fromAmycolatopsis orientalis (formerly, Nocardia orientalis), and the IUPACname is(Sa)-(3S,6R,7R,22R,23S,26S,36R,38aR)-44-{[2-O-(3-amino-2,3,6-trideoxy-3-C-methyl-α-L-lyxo-hexopyranosyl)-β-D-glucopyranosyl]-oxy}-3-(carbamoylmethyl)-10,19-dichloro-2,3,4,5,6,7,23,24,25,26,36,37,38,38a-tetradecahydro-7,22,28,30,32-pentahydroxy-6-[(2R)-4-methyl-2-(methylamino]valeramido]-2,5,24,38,39-pentaoxo-22H-8,11:18,21-dietheno-23,36(iminomethano)-13,16:31,35-di-metheno-1H,16H-[1,6,9]-oxadiazacyclohexadecino-[4,5-m][10,2,16]-benzoxadiazacyclotetracosine-26-carboxylic acid.

Vancomycin hydrochloride is indicated for the treatment of serious orsevere infections caused by susceptible strains of methicillin-resistant(beta-lactam-resistant) staphylococci. It is indicated forpenicillin-allergic patients, for patients who cannot receive or whohave failed to respond to other drugs, including the penicillins orcephalosporins, and for infections caused by vancomycin-susceptibleorganisms that are resistant to other antimicrobial drugs. Relatedglycopeptide antibiotics, such as teicoplanin and telavancin, are alsoused for the treatment of multi-drug resistant gram-positive bacterialinfections.

In pharmaceutical use, Vancomycin is usually administered as thehydrochloride salt, Vancomycin hydrochloride, represented by thefollowing structural formula:

Vancomycin is approved and marketed in the form of capsule andintravenous injection, wherein the injection products are supplied as alyophilized powder or as a frozen solution. Lyophilized powder, prior toadministration to a patient, can be reconstituted with water forinjection and further diluted in an intravenous bag with like saline ordextrose solution. The stability of reconstituted solutions and dilutedsolutions, is limited under refrigerated conditions. Other disadvantagesof diluted formulations include that the pH of the diluted formulationcan vary depending on the choice of the diluent. The dilution step canalso present contamination issues, dosage errors, and thus safetyhazards for the patient. Prior to the patient administration, frozenvancomycin solutions undergo long and cumbersome processes which includethawing at room temperature or under refrigeration, which impedes quickapplication for clinical use. In addition, a thawed vancomycin solutionis chemically stable for only 72 hours at room temperature or for 30days when stored under refrigerated conditions.

In the field of injectable preparations, attempts have been performed tostabilize vancomycin and related glycopeptide antibiotics.

U.S. Pat. No. 4,670,258A discloses protection of vancomycin againstthermal degradation by mixing certain acetylated dipeptides ortripeptides with vancomycin in solution in a narrow molar ratio of 1 to2 moles of peptide to Vancomycin.

U.S. Pat. No. 4,885,275A discloses gel-free concentrated aqueousformulations of vancomycin hydrochloride are provided which comprise theantibiotic salt at a concentration between about 12% and about 50% w/vand a gel-inhibiting compound, e.g., ethanol, at a concentration betweenabout 1% and about 20% v/v.

U.S. Pat. No. 8,778,873B2 discloses a pharmaceutical compositioncontaining two different antibiotics, a glycopeptide and acephalosporin, combined with the help of at least onesolubilizing/stabilizing agent such as sodium bicarbonate or L-arginine.

U.S. Patent Application Publication No. 2014/0260098A1 discloses amethod for a preparation of spray dried vancomycin hydrochloride powder,wherein excipients selected from stabilisers; solubilizers; asaccharide; a polyol; polyethylene glycol 400; and surfactants areadded.

PCT International Application Publication No. WO1997/019690A1 disclose ssolutions of vancomycin hydrochloride comprising about 0.5% and about30% v/v ethanol.

PCT International Application Publication No. WO2001/82971A2 disclosespharmaceutical compositions containing a cyclodextrin and atherapeutically effective amount of a glycopeptide antibiotic or a saltthereof.

PCT International Application Publication No. WO 2014/085526A1 discloseslipid-based vancomycin composition, wherein the composition comprises alipid component, a glycopeptide antibiotic, and an amino acid or aderivative thereof.

European Patent No. EP 1,278,549B1 discloses a pharmaceuticalcomposition comprising a cyclodextrin and a group of glycopeptideantibiotics. The examples involve Telavancin and hydroxypropyl-β-cyclodextrins or sulfobutylether-γ-cyclodextrins.

Japanese Patent No. JP 11,080,021 discloses vancomycin injectionsuppressed in discoloration, comprising water, Vancomycin and 0.1 wt %to 10 wt % amino acids (i.e., Glycine).

Japanese Patent Application Publication No. JP 2008201778A disclosesaqueous vancomycin preparations with addition of glycerol and D-alanineor DL-alanine and/or D-lactic acid or DL-lactic acid.

In 2019, the United States Food and Drug Administration (FDA) approvedVancomycin Hydrochloride injection for intravenous administration (VANCOREADY™) developed by Xellia Pharmaceuticals APS for the treatment of (1)Septicemia, (2) Infective Endocarditis, (3) Skin and Skin StructureInfections, (4) Bone Infections and (5) Lower Respiratory TractInfections. The products are available in single-dose flexible bags, aresterile nonpyrogenic premixed 100 mL, 150 mL, 200 mL, 250 mL, 300 mL,350 mL or 400 mL solutions containing 500 mg, 750 mg, 1 gram, 1.25grams, 1.5 grams, 1.75 grams or 2 grams vancomycin, respectively, asvancomycin hydrochloride. Each 100 mL of solution contains 1.8 mLpolyethylene glycol 400, 1.36 grams N-acetyl-D-alanine, 1.26 gramsL-lysine hydrochloride (monochloride) in water for injection.Hydrochloric acid and sodium hydroxide are used for pH adjustment. ThepH is 4.5 to 5.5 and the osmolarity is 350 mOsmol/L to 475 mOsmol/L.However, VANCO READY™'s product label contains a black box warning forrisk of embryo-fetal toxicity due to excipients, stating that “thisformulation of vancomycin injection, USP is not recommended for useduring pregnancy because it contains the excipients polyethylene glycol(PEG 400) and N-acetyl D-alanine (NADA), which caused fetalmalformations in animal reproduction studies. If use of vancomycin isneeded during pregnancy, use other available formulations ofvancomycin,” and thus, deterring at least women and pregnant women fromusing the VANCO READY™'s product.

Additionally, the Vancomycin composition VANCO READY™ and its use aredescribed in U.S. Pat. Nos. 10,039,804 and 10,188,697, and includestable Vancomycin antibiotic pharmaceutical compositions using asN-acetyl-D-alanine and/or N-acetyl-glycine in the formulation. The useof N-acetyl-D-alanine and/or N-acetyl-glycine in Vancomycin antibioticformulations provides stable solutions. However, substitutingN-acetyl-D-alanine and/or N-acetyl-glycine for other excipients, forexample, N-acetylated dipeptides or tripeptides, causes the preparationto became hazy or leads to rapid degradation of vancomycin and thus suchpreparations are not stable or suitable for use as a pharmaceuticalsolution in a clinical setting.

In light of the above, there is a need for improved glycopeptideantibiotic-related pharmaceutical compositions for intravenousadministration which exhibit improved stability, solubility and/orefficacy, with fewer side effects, including a decreased risk ofembryo-fetal toxicity in pregnant women.

SUMMARY

The inventions described and claimed herein have many attributes andaspects including, but not limited to, those set forth or described orreferenced in this Summary. It is not intended to be all-inclusive andthe inventions described and claimed herein are not limited to or by thefeatures or embodiments identified in this Summary, which is includedfor purposes of illustration only and not restriction.

The invention provides for a stable formulation comprising one or moreglycopeptide antibiotics or a pharmaceutically acceptable salt thereoffor parenteral administration. Particularly, the invention provides fora liquid formulation comprising vancomycin or a pharmaceuticallyacceptable salt thereof, N-acetyl-methionine and one or morepharmaceutically acceptable excipients.

In some aspects, a composition comprising a glycopeptide antibiotic or apharmaceutically acceptable salt thereof for parenteral administration,which can be intramuscular injection, subcutaneous injection,intravenous injection, and intradermal injection.

In some aspects, the formulation comprises a glycopeptide antibiotic ora pharmaceutically acceptable salt thereof in a parenteral composition,wherein the glycopeptide antibiotic is, for example, vancomycin,teicoplanin, ramoplanin, complestatin, corbomycin, bleomycin,oritavancin, dalbavancin or telavancin.

In some aspects, this disclosure provides for a liquid composition forparenteral administration comprising a glycopeptide antibiotic or apharmaceutically acceptable salt thereof in an amount of about 0.1% byweight to about 1.0% by weight, N-acetyl-methionine in an amount ofabout 0.1% by weight to about 5.0% by weight, and one or morepharmaceutically acceptable excipients.

In some aspects, the one or more pharmaceutically acceptable excipientscan be, for example, one or more buffers or buffering agents, one ormore chelating agent, one or more tonicity agents, one or more pHadjusting agents, one or more antioxidants, one or more preservatives,water or a combination thereof. In some aspects, the one or moretonicity agents is sodium chloride.

In some aspects, the glycopeptide antibiotics or a pharmaceuticallyacceptable salt thereof is vancomycin hydrochloride. In some aspects,the concentration of vancomycin hydrochloride is about 5.0 mg/mL. Insome aspects, the N-acetyl-methionine is N-acetyl-D-methionine orN-acetyl-L-methionine. In some aspects, the concentration ofN-acetyl-D-methionine is about 15 mg/mL to about 25 mg/mL. In someaspects, the ratio of vancomycin hydrochloride to N-acetyl-D-methioninepresent in the composition is about 1:1 by weight to about 1:10 byweight. In some aspects, the ratio of vancomycin hydrochloride toN-acetyl-D-methionine present in the composition is about 1:5 by molarto 1:50 by molar.

In some aspects, the formulation does not include N-acetyl D-alanine,polyethylene glycol-400, or both N-acetyl D-alanine and polyethyleneglycol-400.

In some aspects, the formulation is an aqueous solution. In someaspects, the formulation has a pH of about 2 to about 7, preferablyabout 5.0 adjusted with hydrochloric acid solutions or sodium hydroxide.

In some aspects, the formulation is a ready-to-use solution forintravenous, subcutaneous or intramuscular administration.

In some aspects, this disclosure provides for a liquid compositioncomprising:

-   -   vancomycin hydrochloride in an amount of about 0.5% by weight,    -   N-acetyl-D-methionine in an amount of about 1.5% to about 2.5%        by weight,    -   sodium chloride in an amount of about 0.012% by weight,    -   sodium hydroxide or hydrochloride to adjust the composition pH        of about 5.0, and water.

In some aspects, this disclosure provides for a liquid compositionfilled in a vial, an ampoule, a bag, a bottle, a cartridge, or asyringe.

In some aspects, the liquid composition contains about 2.5% or less oftotal impurities.

In some aspects, the liquid composition is stable for at least about 3months at 25±2° C.

In some aspects, this disclosure provides for a process for preparationof a liquid composition for parenteral administration which comprises:

one or more glycopeptide antibiotics or a pharmaceutically acceptablesalt thereof in an amount of about 0.1% by weight to about 1.0% byweight,

N-acetyl-D-methionine in an amount of about 1.5% to about 2.5% byweight,

sodium chloride in an amount of about 0.012% by weight,

sodium hydroxide or hydrochloride to adjust the composition pH of about5.0, and water,

wherein the process comprises a step of sterilizing the liquidcomposition by one or more methods is heat sterilization, gaseoussterilization, filtration sterilization, radiation sterilization, or acombination thereof.

In some aspects, this disclosure provides for a method for treating oneor more bacterial infections or one or more bacterial infection-relatedconditions in a subject in need thereof, the method comprisingadministering to the subject a liquid formulation that comprises:

a therapeutically effective amount of one or more glycopeptideantibiotics or a pharmaceutically acceptable salt thereof,

N-acetyl-methionine (such as N-acetyl-D-methionine,N-acetyl-L-methionine, or a combination thereof), and

one or more pharmaceutically acceptable excipients,

wherein the liquid formulation does not include N-acetyl D-alanine orpolyethylene glycol-400 or both N-acetyl D-alanine and polyethyleneglycol-400.

In some aspects, the subject is male, female, pregnant female, adult,child, mammal, human, or a combination thereof.

In some aspects, the one or more bacterial infections is one or moreskin and/or skin structure infections, one or more bone infections, oneor more lower respiratory tract infections, or a combination thereof. Insome aspects, the one or more bacterial infection-related conditions issepticemia, infective endocarditis, or a combination thereof.

In some aspects, this disclosure provides for a method of treating oneor more bacterial infections or one or more bacterial infection-relatedconditions in a subject in need thereof, the method comprisingadministering to the subject a liquid formulation that comprises:

-   -   (a) a therapeutically effective amount of one or more        glycopeptide antibiotics or a pharmaceutically acceptable salt        thereof,    -   (b) N-acetyl-methionine and    -   (c) one or more pharmaceutically acceptable excipients,

wherein the liquid formulation does not include N-acetyl D-alanine orpolyethylene glycol-400 or both N-acetyl D-alanine and polyethyleneglycol-400.

In some aspects, this disclosure provides for a method of treating aninfectious disease in a subject in need thereof, the method comprisingadministering to the subject a liquid formulation that comprises:

-   -   (a) a therapeutically effective amount of one or more        glycopeptide antibiotics or a pharmaceutically acceptable salt        thereof,    -   (b) N-acetyl-methionine, and    -   (c) one or more pharmaceutically acceptable excipients,

wherein the liquid formulation does not include N-acetyl D-alanine orpolyethylene glycol-400 or both N-acetyl D-alanine and polyethyleneglycol-400.

In some aspects, the infectious disease is caused byMethicillin-resistant Staphylococcus aureus (MRSA), enterococci,vancomycin-resistant enterococci (VRE), coagulase negativestaphylococci, or a combination thereof.

In some aspects, this disclosure provides for a method of treating asubject suffering from an infection caused by Gram-positive organisms,the method comprising administering to the subject in need thereof aliquid formulation that comprises:

-   -   (a) a therapeutically effective amount of one or more        glycopeptide antibiotics or a pharmaceutically acceptable salt        thereof,    -   (b) N-acetyl-methionine, and    -   (c) one or more pharmaceutically acceptable excipients,    -   wherein the liquid formulation does not include N-acetyl        D-alanine or polyethylene glycol-400 or both N-acetyl D-alanine        and polyethylene glycol-400.

In some aspects, the Gram-positive organisms is Staphylococcus,Streptococcus spp., Enterococcus spp. or a combination thereof. In someaspects, the infection caused by Gram-positive organisms is astaphylococcal infection. In some aspects, the staphylococcal infectionis staphylococcal endocarditis, staphylococcal septicemia, or acombination thereof.

In some aspects, this disclosure provides for a method of treating asubject suffering from an inflammatory disease, the method comprisingadministering to the subject in need thereof a liquid formulation thatcomprises:

-   -   (a) a therapeutically effective amount of one or more        glycopeptide antibiotics or a pharmaceutically acceptable salt        thereof,    -   (b) N-acetyl-methionine, and    -   (c) one or more pharmaceutically acceptable excipients,

wherein the liquid formulation does not include N-acetyl D-alanine orpolyethylene glycol-400 or both N-acetyl D-alanine and polyethyleneglycol-400.

In some aspects, the inflammatory disease is enterocolitis, rheumaticfever, endocarditis, colitis, or a combination thereof.

In some aspects, the liquid composition administered to the subject inneed thereof comprises:

one or more glycopeptide antibiotics or a pharmaceutically acceptablesalt thereof in an amount of about 0.1% by weight to about 1.0% byweight of the composition,

wherein the weight ratio of glycopeptide antibiotics or thepharmaceutically acceptable salt thereof to N-acetyl-methionine (such asN-acetyl-D-methionine, N-acetyl-L-methionine, or a combination thereof)present in the composition is about 1:1 by weight to about 1:100 byweight, 1:1 by weight to about 1:50 by weight, or 1:1 by weight to 1:10by weight

In some aspects, a liquid composition administered to a subject in needthereof comprises:

one or more glycopeptide antibiotics or a pharmaceutically acceptablesalt thereof; and

N-acetyl-methionine;

wherein the molar ratio of glycopeptide antibiotics or thepharmaceutically acceptable salt thereof to the N-acetyl-methionine(such as N-acetyl-D-methionine, N-acetyl-L-methionine, or a combinationthereof) present in the liquid composition is about 1:5 by molar toabout 1:50 by molar.

In some aspects, the one or more glycopeptide antibiotics or apharmaceutically acceptable salt thereof in the liquid compositionadministered to a subject in need thereof is vancomycin.

In some aspects, the maximum daily intake (MDI) of N-acetyl-D-methionineis 10 grams/day based on a 100 mL drug product bag containing 0.5 gramsvancomycin and 2.5 grams N-acetyl-D-methionine.

In some aspects, the one or more one or more glycopeptide antibiotics ora pharmaceutically acceptable salt thereof is vancomycin, the maximumdaily dose (MDD) of vancomycin is 2 grams/day for 10 days or less.

In some aspects, this disclosure provides for a process for preparing aliquid composition for parenteral administration, the processcomprising:

(a) adding a glycopeptide or pharmaceutically acceptable salt tosterilized water;

(b) stirring the solution until the glycopeptide or pharmaceuticallyacceptable salt is fully dissolved by visual inspection;

(c) adding N-acetyl-D-methionine (NADM) to the solution and stirringuntil the NADM is fully dissolved by visual inspection;

(d) adding sodium chloride and stirring until the components of thesolution are fully dissolved by visual inspection;

(e) adjusting the pH to about 5.0 using Hydrochloric acid or sodiumhydroxide;

(f) QS with sterilized water suitable for injection to a selected totalvolume; and

(g) stirring for an additional selected amount of time to form aprepared composition.

In some aspects, the sterilized water is prepared by one or more of heatsterilization, gaseous sterilization, filtration sterilization, orradiation sterilization.

In some aspects, the preparation process can further comprise the stepof:

(h) aseptically filling the prepared solution into sterile bags ofappropriate size

In some aspects, the relative amount of the one or more glycopeptideantibiotics or a pharmaceutically acceptable salt thereof in theprepared composition is about 0.1% by weight to about 1.0% by weight.

In some aspects, the relative amount of the N-acetyl-methionine in theprepared composition is about 1.5% to about 2.5% by weight.

In some aspects, the relative amount of the sodium chloride in theprepared solution is about 0.012% by weight.

DETAILED DESCRIPTION

Vancomycin and related glycopeptide parenteral formulations whichexhibit a safe and effective use of vancomycin to the entire treatmentspectrum including the use of vancomycin during pregnancy are an unmetneed. The inventors have determined that there is an enduring need todevelop vancomycin formulation that can provides an alternative toexisting formulations, and which remain stable and soluble in solutionover extended periods of time to allow for clinical utility. Theinventors have surprisingly found that by use of N-acetyl-methionine(such as N-acetyl-D-methionine, N-acetyl-L-methionine, or a combinationthereof) in the formulations provide stable vancomycin formulationswhich remain suitable for administration to a subject throughout theproduct shelf life, can be used in treating one or more bacterialinfections in the subject, and can be used during pregnancy.

N-acetyl-methionine is a chiral molecule with D (NADM) and L (NALM)forms, consistent with the D and L forms of methionine. NADM is used innonclinical research as a preservative/stabilizer. The NALM form is usedwidely in food and medicine as a stable chemical precursor and as thealternative form of the essential amino acid L-methionine.

The toxicity of NADM and NALM appears to suggest that NADM is less toxicthan NALM and is therefore a suitable component of vancomycincompositions. NADM in orally-dosed pigs (˜382 milligrams/kilogram bodyweight [mg/kg]), appeared rapidly in the plasma (peak plasmaconcentration achieved 15 minutes after dosing), with NADM onlyminimally hydrolyzed to D- and L-methionine and thought to be excretedmostly intact in the urine (Daabees, T. et al., “Portal and vena cavalplasma methionine concentrations in young pigs administeredL-methionine, NALM and NADM,” J. Nutrition, 114:1541-1547 (1984)(Daabees 1984); Friedmann, M. et al., “Nutritional value and safety ofmethionine derivatives, isomeric dipeptides and hydroxy analogs inmice,” J. Nutrition, 118:388-397 (1988) (Friedmann 1988). This pathwayhas been confirmed by other studies where orally orintraperitoneally-(IP) dosed NADM in rodents was not a significantsource of either D- or L-methionine (Boggs, R. et al., “Acetylmethionineas a source of methionine in the rat,” J. Nutrition, 105:326-330 (1975)(Boggs 1975); Rotruck, J. et al., “Comparative metabolism ofL-methionine and N-acetylated derivative s of methionine,” J.Nutrition., 105(3):331-337 (1975) (Rotruck 1975); Baker, D. H.,“Efficacy of the D- and L-isomers of N-acetylmethionine for chicks feddiets containing either crystalline amino acids or intact protein,” J.Nutrition, 109(6):970-974 (1979) (Baker 1979)). In rodents and pigs somelow levels of L-methionine may be produced from D-methionine (Cho, E. etal., “D-methionine utilisation during parenteral nutrition in rats,” J.Nutrition, 109(6):1086-1093 (1979) (Cho 1979)). Primates, however, arenot able to convert D-methionine to the active form of L-methionine;therefore, an oral human dose of NADM would not produce L-methionine.However, NALM, unlike NADM, is absorbed rapidly and is completelyhydrolyzed to L-methionine and acetic acid (and ultimately to carbondioxide) via the action of acylases (Daabees 1984; Friedman 1988; Baker1979; European Food Safety Agency (EFSA). 2003. NALM for use in foodsfor special medical purposes. EFSA Journal. 22:1-10 (EFSA 2003)).Subsequently, L-methionine is utilized as an essential amino acid invarious biochemical processes (Rotruck 1975). While no acute lethalstudies have been performed with NADM directly, it is known that NALMhas an LD50 (rats, IV) of 435 mg/kg, and N-acetyl-DL-methionine has anLD50 (rats, IP) of 6700 mg/kg. The significant difference between theracemate (which comprises 50/50 NADM and NALM) and NALM alone suggeststhat NADM is less toxic than NALM and would therefore be a suitablecomponent of a vancomycin composition for IP administration.

In some embodiments, this disclosure provides for a stable formulationor pharmaceutical composition comprising one or more glycopeptideantibiotics or a pharmaceutically acceptable salt thereof for parenteraladministration. In particular, the invention provides a liquidformulation comprising vancomycin or a pharmaceutically acceptable saltthereof, N-acetyl-methionine (such as N-acetyl-D-methionine,N-acetyl-L-methionine, or a combination thereof), and one or morepharmaceutically acceptable excipients.

In some embodiments, a formulation or composition comprising one or moreglycopeptide antibiotics or a pharmaceutically acceptable salt thereofand N-acetyl-methionine (such as N-acetyl-D-methionine,N-acetyl-L-methionine, or a combination thereof). In some embodiments,the composition may be in the form of a ready-to-use liquid formulation.In some embodiments, the formulation or composition is aqueous.

In some embodiments, the N-acetyl-methionine used in the formulation orcomposition may be in the form of D or L isomers (N-acetyl-D-methionineor N-acetyl-L-methionine), or both.

In some embodiments, the weight ratio of one or more glycopeptideantibiotics or a pharmaceutically acceptable salt thereof toN-acetyl-methionine (such as N-acetyl-D-methionine,N-acetyl-L-methionine, or a combination thereof) present in theformulation or composition may be about 1:1 by weight to about 1:100 byweight, 1:1 by weight to about 1:50 by weight, or 1:1 by weight to 1:10by weight. In some embodiments, weight ratio of one or more glycopeptideantibiotics or a pharmaceutically acceptable salt thereof toN-acetyl-methionine (such as N-acetyl-D-methionine,N-acetyl-L-methionine, or a combination thereof) present in theformulation or composition may be about 1:3 by weight to about 1:5 byweight. In some embodiments, the molar ratio of one or more glycopeptideantibiotics or a pharmaceutically acceptable salt thereof toN-acetyl-methionine (such as N-acetyl-D-methionine,N-acetyl-L-methionine, or a combination thereof) present in theformulation or composition may be about 1:5 by molar to about 1:50 bymolar, or about 1:5 by molar, about 1:6 by molar, about 1:7 by molar,about 1:8 by molar, about 1:9 by molar, about 1:10 by molar, about 1:11by molar, about 1:12 by molar, about 1:13 by molar, about 1:14 by molar,about 1:15 by molar, about 1:16 by molar, about 1:17 by molar, about1:18 by molar, about 1:19 by molar, about 1:20 by molar, about 1:21 bymolar, about 1:22 by molar, about 1:23 by molar, about 1:24 by molar,about 1:25 by molar, about 1:26 by molar, about 1:27 by molar, about1:28 by molar, about 1:29 by molar, about 1:30 by molar, about 1:31 bymolar, about 1:32 by molar, about 1:33 by molar, about 1:34 by molar,about 1:35 by molar, about 1:36 by molar, about 1:37 by molar, about1:38 by molar, about 1:39 by molar, about 1:40 by molar, about 1:41 bymolar, about 1:42 by molar, about 1:43 by molar, about 1:44 by molar,about 1:45 by molar, about 1:46 by molar, about 1:47 by molar, about1:48 by molar, about 1:49 by molar, or about 1:50 by molar.

In some embodiments, the formulation or composition comprises one ormore glycopeptide antibiotics or a pharmaceutically acceptable saltthereof and N-acetyl-methionine (such as N-acetyl-D-methionine,N-acetyl-L-methionine, or a combination thereof), wherein theformulation or composition does not include N-acetyl D-alanine, orpolyethylene glycol-400 or both N-acetyl D-alanine and polyethyleneglycol-400.

In some embodiments, the formulation or composition comprises one ormore glycopeptide antibiotics or a pharmaceutically acceptable saltthereof and N-acetyl-methionine (such as N-acetyl-D-methionine,N-acetyl-L-methionine, or a combination thereof) and one or more aminoacids. In some embodiments, the one or more amino acids is glycine,alanine, serine, leucine, valine, lysine, arginine, ornithine, in theforms of L-form and/or D-form, or a combination thereof.

In some embodiments, the formulation or composition comprises one ormore glycopeptide antibiotics or a pharmaceutically acceptable saltthereof and N-acetyl-methionine (such as N-acetyl-D-methionine,N-acetyl-L-methionine, or a combination thereof), wherein theformulation or composition is devoid of an amino acid.

In some embodiments, the formulation or composition comprises one ormore glycopeptide antibiotics or a pharmaceutically acceptable saltthereof in an amount of about 0.1% by weight to about 1.0% by weight.

In some embodiments, the formulation or composition compriseN-acetyl-methionine (such as N-acetyl-D-methionine,N-acetyl-L-methionine, or a combination thereof) in an amount of about0.1% by weight to about 5.0% by weight.

In some embodiments, the formulation or composition is in the form of asolution, a suspension or a dispersion.

In some embodiments, the formulation or composition has a pH of about 2to about 7, preferably about 5.0 adjusted with one or more hydrochloricacid solutions or one or more sodium hydroxide solutions.

In some embodiments, the formulation or composition is preferablyaqueous and typically may include about 50%, about 60%, about 70%, about80%, about 85%, about 90%, about 95%, about 98% or about 99% by weightwater.

In some embodiments, suitable diluents for the disclosed formulation andcompositions herein include any known diluent acceptable forpharmaceutical use (example, intravenous administration); for example,water, physiological saline, 5% dextrose solution, lactated Ringer'ssolution, or a combination thereof.

In some embodiments, the formulation or composition may be suitable forstorage in vials, syringes or infusion containers, such as, for example,bottles, infusion bags or the like, and may show chemical and physicalstability when stored at temperatures from about 2° C. to about 30° C.

In some embodiments, the formulation or composition compriseN-acetyl-methionine (such as N-acetyl-D-methionine,N-acetyl-L-methionine, or a combination thereof), and further compriseone or more pharmaceutically acceptable excipients, the one or morepharmaceutically acceptable excipients is one or more tonicity agents,one or more preservatives, one or more surfactants, one or morebuffering agents, one or more pH-adjusting agents, one or more vehicles,or a combination thereof.

In some embodiments, the formulation or composition retains at leastabout 90% w/w of the potency of the one or more glycopeptide antibioticsor a pharmaceutically acceptable salt thereof when stored at about 25°C. and about 60% relative humidity or at about 40° C. and about 75%relative humidity for about 3 months.

In some embodiments, the formulation or composition exhibits stabilitythroughout the shelf life as the impurities observed are well below thespecified limits, and the stability may be an improvement from VANCOREADY™'s stability. Stability of the formulation or composition can beexpressed as the amount of glycopeptide antibiotic, for example,vancomycin, impurities present after a predetermined time period.

In some embodiments, a stable liquid formulations comprising vancomycinor a pharmaceutically acceptable salt thereof, N-acetyl-methionine (suchas N-acetyl-D-methionine, N-acetyl-L-methionine, or a combinationthereof) and one or more pharmaceutically acceptable excipients.

In some embodiments, a liquid formulation comprising vancomycin or apharmaceutically acceptable salt thereof, N-acetyl-methionine (such asN-acetyl-D-methionine, N-acetyl-L-methionine, or a combination thereof)and one or more pharmaceutically acceptable excipients, wherein theliquid formulation is devoid of N-acetyl D-alanine or polyethyleneglycol-400 or both.

In some embodiments, there is provided premixed ready-to-use injectablecompositions of one or more glycopeptide antibiotics or apharmaceutically acceptable salt thereof, N-acetyl-methionine (such asN-acetyl-D-methionine, N-acetyl-L-methionine, or a combination thereof)and one or more pharmaceutically acceptable excipients, to avoid theinconvenience of diluting a concentrated small volume parenteralformulation into infusion diluents prior to infusion, and to eliminatethe risk of microbiological contamination during aseptic handling andany potential calculation or dilution error.

In some embodiments, a stable ready-to-use liquid formulation comprisingvancomycin hydrochloride in an amount of about 0.1% by weight to about1.0% by weight, N-acetyl-methionine (such as N-acetyl-D-methionine,N-acetyl-L-methionine, or a combination thereof) in an amount of about0.1% by weight to about 5.0% by weight, sodium chloride in an amount ofabout 0.005% by weight to about 0.05% by weight, sodium hydroxide orhydrochloride to adjust the composition pH of about 5.0, and water forinjection.

In some embodiments, a stable ready-to-use liquid formulation comprisingvancomycin hydrochloride in an amount of about 0.51% by weight,N-acetyl-D-methionine in an amount of about 2.5% by weight, sodiumchloride in an amount of about 0.012% by weight, sodium hydroxide orhydrochloride to adjust the composition pH of about 5.0, and water forinjection.

In some embodiments, a stable liquid formulation comprising vancomycinhydrochloride in an amount of about 0.51% by weight,N-acetyl-D-methionine in an amount of about 1.5% by weight, sodiumchloride in an amount of about 0.012% by weight, sodium hydroxide orhydrochloride to adjust the composition pH of about 5.0, and water forinjection.

In some embodiments, a stable liquid formulation comprising vancomycinor a pharmaceutically acceptable salt thereof, N-acetyl-D-methionine andone or more pharmaceutically acceptable excipients, wherein the obtainedformulation exhibits stability throughout the shelf life as theimpurities observed are well below the specified limits. Such stabilitymay be an improvement relative to VANCO READY™'s stability.

In some embodiments, a process for preparing a liquid formulationcomprising vancomycin or a pharmaceutically acceptable salt thereof,N-acetyl-methionine (such as N-acetyl-D-methionine,N-acetyl-L-methionine, or a combination thereof) and one or morepharmaceutically acceptable excipients.

In some embodiments, the process for preparing and sterilizing theliquid formulation may provide a reduction in the amount of relatedcompounds and impurities associated with the formulations on storage.

In some embodiments, the sterilisation is carried out by using one ormore methods, such methods include, but are not limited to, heatsterilization, gaseous sterilization, filtration sterilization,radiation sterilization, or a combination thereof.

In some embodiments, a method for treating one or more bacterialinfections in a subject in need thereof, the method comprisingadministering to the subject a liquid formulation comprising atherapeutically effective amount of one or more glycopeptide antibioticsor a pharmaceutically acceptable salt thereof, N-acetyl-methionine (suchas N-acetyl-D-methionine, N-acetyl-L-methionine, or a combinationthereof) and one or more pharmaceutically acceptable excipients.

In some embodiments, a method for treating one or more bacterialinfections in a subject in need thereof, the method comprisingadministering to the subject a liquid formulation comprising atherapeutically effective amount of one or more glycopeptide antibioticsor a pharmaceutically acceptable salt thereof, N-acetyl-methionine (suchas N-acetyl-D-methionine, N-acetyl-L-methionine, or a combinationthereof) and one or more pharmaceutically acceptable excipients, whereinthe composition is devoid of N-acetyl D-alanine or polyethyleneglycol-400 or both.

In some embodiments, the subject is male, female, pregnant female,adult, child, mammal, human, or a combination thereof.

In some embodiments, the one or more bacterial infections is one or moreskin and/or skin structure infections, one or more bone infections, oneor more lower respiratory tract infections, or a combination thereof. Insome aspects, the one or more bacterial infection-related conditions issepticemia, infective endocarditis, or a combination thereof.

In some embodiments, the maximum daily intake (MDI) ofN-acetyl-D-methionine is 10 grams/day based on a 100 mL drug product bagcontaining 0.5 grams vancomycin and 2.5 grams N-acetyl-D-methionine.

In some embodiments, the one or more one or more glycopeptideantibiotics or a pharmaceutically acceptable salt thereof is vancomycin,the maximum daily dose (MDD) of vancomycin is 2 grams/day for 10 days orless.

Definitions

General terms used in formula can be defined as follows; however, themeaning stated should not be interpreted as limiting the scope of theterm per se.

As used herein, the recitation of a numerical range for a variable isintended to convey that the invention may be practiced with the variableequal to any of the values within that range. Thus, for a variable thatis inherently discrete, the variable can be equal to any integer valueof the numerical range, including the end-points of the range.Similarly, for a variable, which is inherently continuous, the variablecan be equal to any real value of the numerical range, including theend-points of the range. As an example, a variable which is described ashaving values between 0 and 2, can be 0, 1 or 2 for variables which areinherently discrete, and can be 0.0, 0.1, 0.01, 0.001, or any other realvalue, for variables which are inherently continuous.

As used herein, the term “glycopeptide antibiotics” refers to moleculeswhich contain a heptapeptide structure providing specific affinity forthe D-alanyl-D-Alanine terminus of the peptidoglycan pentapeptideincluding, for example, vancomycin, telavancin, oritavancin, teicoplaninand dalbavancin (See, e.g., Parenti & Cavalleri, “Proposal to Name theVancomycin-Ristocetin Like Glycopeptides as Dalbaheptides,” J.Antibiotics, 4(12):1882 (December 1989)). Structures for some of thosemolecules are shown in FIG. 1, which is adapted from Kang, H-K. et al.,“Glycopeptide Antibiotics: Structure and Mechanisms of Action,” J.Bacteriol. Virol., 45(2):67-78 (2015).

As used herein, the term “vancomycin” refers to not only vancomycin perse, but also its other pharmaceutically acceptable salts,pharmaceutically acceptable solvates, pharmaceutically acceptablehydrates, pharmaceutically acceptable enantiomers, pharmaceuticallyacceptable derivatives, pharmaceutically acceptable polymorphs andpharmaceutically acceptable prodrugs thereof. The formulations of theinvention preferably comprise vancomycin hydrochloride.

As used herein, the term “Methionine” refers to the sulfur-containingessential amino acid that improves muscle tone and elasticity of theskin, hair and strengthens nails. It is one of the nine essential aminoacids in humans. L-Methionine is the natural-occurring amino acid.D-methionine may be eliminated unchanged in urine or feces.

As used herein, the term “D-alanine” is a non-essential amino acid inhumans, is used for protein construction, and is involved in themetabolism of tryptophan and vitamin pyridoxine. D-Alanine is thenon-proteinogenic form of alanine which is used in bacterial cell wallbiosynthesis, and helps in the metabolism of sugars and organic acids.

As used herein, the term “N-acetyl-methionine” is a compound representedby the following structure:

N-acetyl-methionine can exist as an acid or in deprotonated form. Theterm “N-acetyl-methionine” is also meant to cover any salt thereof,especially pharmaceutically acceptable salts. N-acetyl-methionine is achiral molecule with D (NADM) and L (NALM) forms, consistent with the Dand L forms of methionine represented by the following structure:

NADM is used in nonclinical research and as a preservative/stabilizer.The NALM form is used widely in food and medicine as a stable chemicalprecursor and as the alternative form of the essential amino acid Lmethionine. N-acetyl-methionine can be N-acetyl-D-methionine,N-acetyl-L-methionine, or a combination thereof.

The compounds of the invention may have one or more chiral centers. Theabsolute stereochemistry at each chiral center may be ‘R’ or ‘S’. Thecompounds of the invention include all diastereomers and enantiomers andmixtures thereof. Unless specifically mentioned otherwise, reference toone stereoisomer applies to any of the possible stereoisomers. Wheneverthe stereoisomeric composition is unspecified, it is to be understoodthat all possible stereoisomers are included.

As used herein, the term “stereoisomer” refers to a compound made up ofthe same atoms bonded by the same bonds but having differentthree-dimensional structures which are not interchangeable. Thethree-dimensional structures are called configurations. As used herein,the term “enantiomer” refers to two stereoisomers whose molecules arenon-superimposable mirror images of one another. The term “chiralcenter” refers to a carbon atom to which four different groups areattached. As used herein, the term “diastereomers” refers tostereoisomers which are not enantiomers. The terms “racemate” or“racemic mixture” refer to a mixture of equal parts of enantiomers.

As used herein, the term “treating” or “treatment” of a state, disorderor condition includes: (a) preventing or delaying the appearance ofclinical symptoms of the state, disorder or condition developing in asubject that may be afflicted with or predisposed to the state, disorderor condition but does not yet experience or display clinical orsubclinical symptoms of the state, disorder or condition; (b) inhibitingthe state, disorder or condition, i.e., arresting or reducing thedevelopment of the disease or at least one clinical or subclinicalsymptom thereof; (c) lessening the disease, disorder or condition or atleast one of its clinical or subclinical symptoms or (d) relieving thedisease, i.e., causing regression or amelioration of the state, disorderor condition or at least one of its clinical or subclinical symptoms.

As used herein, the terms “treat,” “ameliorate,” and “inhibit,” andwords stemming therefrom, as used herein, do not necessarily imply 100%or complete treatment, amelioration, or inhibition. Rather, there arevarying degrees of treatment, amelioration, and inhibition of which oneof ordinary skill in the art recognizes as having a potential benefit ortherapeutic effect. In this respect, the disclosed methods can provideany amount of any level of treatment, amelioration, or inhibition of thedisorder in an animal, particularly, a mammal (such as a human). Forexample, a disorder, including symptoms and/or conditions thereof, maybe reduced by, for example, about 100%, about 90%, about 80%, about 70%,about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%.Furthermore, the treatment, amelioration, or inhibition provided by theinventive method can include treatment, amelioration, or inhibition ofone or more conditions or symptoms of the disorder, e.g., bacterialinfection. Also, for purposes herein, “treatment,” “amelioration,” or“inhibition” can encompass delaying the onset of the disorder, or asymptom or condition thereof.

As used herein, the term “inhibitor” refers to a molecule that binds toan enzyme to inhibit the activity of said enzyme either partially orcompletely.

As used herein, the terms “patient” and “subject” are interchangeableand can be taken to mean any living organism that can be treated withthe pharmaceutical compositions disclosed herein. The terms “patient:and “subject” include mammals (such as primates or humans) and otheranimals, such as domestic animals (e.g., household pets including catsand dogs, horses, cattle, pigs, chickens, turkeys, and sheep) andnon-domestic animals (such as wildlife).

As used herein, the term “therapeutically effective amount” refers tothe amount of a compound that, when administered to a subject fortreating a disease, disorder or condition, is sufficient to cause theeffect in the subject, which is the purpose of the administration. The“therapeutically effective amount” will vary depending on the compound,route of administration, the disease and its severity and the age,weight, physical condition and responsiveness of the subject to betreated.

As used herein, the term “formulation” is interchangeable withpharmaceutical formulation, liquid composition, liquid formulation,composition and solution and refers to preparations comprisingvancomycin or a pharmaceutically acceptable salt; in a form suitable forparenteral administration to a patient or subject.

As used herein, the term “ready-to-use” refers to a liquid forparenteral administration that is not obtained by reconstituting alyophilized product. The liquid ready-to-use solutions as per thisinvention are not diluted with any diluent before administration.

As used herein, the term “stable formulation” as used herein, refers toany preparation of one or more glycopeptide antibiotics or apharmaceutically acceptable salt thereof having sufficient physical andchemical stability to allow storage at a convenient temperature, such asbetween about 0° C. and about 50° C., for a commercially reasonableperiod of time. The term “physical stability” refers to maintenance ofcolor, dissolved oxygen level, head space oxygen level, and particulatematter and the term “chemical stability” relates to formation ofdrug-related impurities in terms of total impurity, single maximumindividual impurity and maximum individual unknown impurity. For thepurpose of the present invention chemical stability also includesmaintenance of pH of the finished formulation. For pharmaceuticalproducts, stability is required for commercially relevant times aftermanufacturing, such as for about 6, 12, 18, 24 or 36 months, duringwhich a product is kept in its original packaging under specifiedstorage condition.

As used herein, the term “shelf life” refers to the amount of time theformulations may be stored without loss of potency and/or dissolutionprofile. Preferably, the shelf life refers to the amount of time theformulations may be stored without a loss of more than about 2%, about5%, about 8% or about 10% of the potency and/or dissolution.

As used herein, the term “about” is intended to qualify the numericalvalues which it modifies, denoting such a value as variable within amargin of error, typically the degree of uncertainty in the measurementsystem (e.g., pipette error). When no particular margin of error, suchas a standard deviation to a mean value, is recited, the term “about”means plus or minus 10% of the numerical value of the number with whichit is being used. By way of example, “about 50%” means in the range of45% to 55%.

As used herein, the term “pH” as used herein, is the conventionalmeasurement unit of hydrogen ion activity in a solution at roomtemperature (25° C.) unless other temperature is specified. A preferredpH range for the formulations of the invention is from about 2.0 toabout 6.0; in particular from about 2.5 to about 5.5 and specificallyfrom about 4.5 to about 5.5. The pH of the glycopeptide antibioticformulations or compositions will be affected by the concentration ofeach of the ingredients. In some embodiments, the pH of the compositionsdescribed herein can be 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8,4.9, 5.0, or between any of the aforementioned values. The pH of thesolutions is preferably measured at room temperature.

The pH of the glycopeptide antibiotic solutions according to theinvention can be adjusted in any suitable manner by means of theaddition of pH adjusting agents in an amount sufficient to maintain a pHof the compositions from about 2.0 to about 7.0, for example by additionof aqueous hydrochloric acid solutions or aqueous sodium hydroxidesolutions. Such solutions can be diluted or concentrated. Thus, suitablepH adjusting agents include, but are not limited to 0.01M hydrochloricacid, 0.1 M hydrochloric acid, 1 M hydrochloric acid, 2 M hydrochloricacid, 3 M hydrochloric acid, 4 M hydrochloric acid, 5 M hydrochloricacid, 6 M hydrochloric acid, 0.01 M sodium hydroxide, 0.1 M sodiumhydroxide, 1 M sodium hydroxide, 2 M sodium hydroxide, 3 M sodiumhydroxide, 4 M sodium hydroxide, 5 M sodium hydroxide and 6 M sodiumhydroxide. Thus, suitable pH adjusting agents include, but are notlimited to 1 M hydrochloric acid and 1 M sodium hydroxide.

The buffer(s) or pH-adjusting agent(s) in the formulations orcompositions are used to adjust the pH to a desirable range. Exemplarybuffers include sodium hydroxide, sodium carbonate, sodium bicarbonate,potassium hydroxide, ammonium carbonate, hydrochloric acid, citric acid,lactic acid, phosphoric acid, sodium phosphate, sulfuric acid and thelike.

As used herein, the term “pharmaceutically acceptable excipients” refersto an ingredient, other than an active ingredient, that can solubilizeor stabilize an active ingredient. Pharmaceutically acceptableexcipients can include or exclude: buffers or buffering agents,chelating agents (e.g., EDTA), tonicity agents, pH adjusting agents,antioxidants, preservatives and water.

As used herein, the term “pharmaceutically acceptable salt” refers topharmaceutically acceptable organic, or inorganic, salts of a compoundof the invention. Exemplary salts include, but are not limited to, aminoacid salts, sulfate, citrate, acetate, oxalate, chloride, bromide,iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate,lactate, salicylate, acid citrate, tartrate, oleate, tannate,pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate,fumarate, gluconate, glucuronate, saccharate, formate, benzoate,glutamate, methanesulfonate (“mesylate”), ethanesulfonate,benzenesulfonate, p-toluenesulfonate, and pamoate (i.e.,1,1′-methylene-bis(2-hydroxy-3-naphthoate)) salts. A pharmaceuticallyacceptable salt may involve the inclusion of another molecule, such asan acetate ion, a succinate ion, or other counter ion. In someembodiments, the counter ion is any organic, or inorganic, moiety thatstabilizes the charge on the parent compound. Furthermore, apharmaceutically acceptable salt may have more than one charged atom inits structure. Instances where multiple charged atoms are part of thepharmaceutically acceptable salt can have multiple counter ions. Hence,a pharmaceutically acceptable salt can have one or more charged atomsand/or one or more counter ion.

As used herein, the term “disease state” refers to all disease statesthat are generally acknowledged in the art to be usefully treated with abroad spectrum antibacterial in general, and those disease states thathave been found to be usefully treated by the specific antibacterials ofthis invention. Such disease states include, but are not limited to,treatment of a mammal afflicted with pathogenic bacteria, in particularstaphylococci (methicillin sensitive and resistant), streptococci(penicillin sensitive and resistant), enterococci (vancomycin sensitiveand resistant), and Clostridium difficile.

As used herein, the term “therapeutically effective amount” refers tothat amount which is sufficient to effect treatment, as defined herein,when administered to a mammal in need of such treatment. Thetherapeutically effective amount will vary depending on the subject anddisease state being treated, the severity of the affliction and themanner of administration, and may be determined routinely by one ofordinary skill in the art.

As used herein, the term “Biological effect” refers to, but is notlimited to, increased affinity, increased selectivity, increasedpotency, increased efficacy, increased duration of action, decreasedtoxicity, and the like.

Compositions

The compositions of this disclosure include stable liquid formulationsor compositions comprising comprises one or more glycopeptideantibiotics (such as vancomycin) or a pharmaceutically acceptable saltthereof and N-acetyl-methionine. In some embodiments, theN-acetyl-methionine is N-acetyl-D-methionine, N-acetyl-L-methionine, ora combination thereof.

The stable liquid vancomycin formulation or composition refers to aformulation or composition that retains at least about 90%, or aboutleast about 95%, or at least about 96%, or at least about 98%, of thelabelled concentration of vancomycin or pharmaceutically acceptable saltthereof after storage under typical and/or accelerated conditions.

The formulations or compositions include vancomycin or apharmaceutically acceptable salt suitable for parenteral administrationand one or more pharmaceutically acceptable excipients selected frombuffers or buffering agents, chelating agent, antioxidant, tonicityagents, pH adjusting agents, preservatives and solvent, wherein theformulation contains N-acetyl-methionine (such as N-acetyl-D-methionine,N-acetyl-L-methionine, or a combination thereof).

The tonicity agents are used in liquid formulations or compositions toadjust the formulation or composition to be within the desired isotonicrange. Exemplary tonicity agents include, but are not limited to, sodiumchloride, potassium chloride, dextrose, glucose, glycerol, and mannitol.The tonicity agents are in the amount of about 0.01% by weight to about0.8% by weight.

The preservatives in the liquid formulations or compositions are used toinhibit the microbial growth. Suitable preservatives include, but arenot limited to, quaternary ammonium salts such as benzalkonium chlorideand benzethonium chloride; hydrogen peroxide; sorbic acid; biquanides;cationic compounds such as chlorhexidine gluconate; p-hydroxybenzoatessuch as methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propylp-hydroxybenzoate and butyl p-hydroxybenzoate; alcohol compounds such aschlorobutanol and benzyl alcohol; sodium dehydroacetate; thiomersal andthe like.

Chelating agents are used in the compositions to enhance preservativeeffectiveness by forming stable water-soluble complexes (chelates) withalkaline earth and heavy metal ions. Exemplary chelating agents include,but are not limited to, ethylenediaminetetraacetic acid (EDTA), or saltsthereof. The chelating agent typically is present in an amount fromabout 0.001 by weight to about 0.1% by weight. In the case of EDTA, thechelating agent is preferably present at a concentration of about 0.025%by weight.

In some embodiments, the formulations and compositions of thisdisclosure may further comprise an amino acid. In one embodiment, thestable or stabilized glycopeptide antibiotic compositions according tothe invention comprise vancomycin and include optionally an amino acid.The preferred amino acids include alanine, serine, leucine, valine,lysine, arginine and ornithine. The most preferred amino acids includeD-alanine, D-serine, D-leucine, D-valine, L-lysine, D-lysine,L-ornithine, D-ornithine or L-arginine. The amino acids can be added tothe formulations or compositions in the form of pharmaceuticallyacceptable salts.

The formulations or compositions can be prepared by using any suitabletechnique, many of which are known to those skilled in the art and canbe combined in any order.

The ratio of the glycopeptide antibiotic to N-acetyl-methionine (such asN-acetyl-D-methionine, N-acetyl-L-methionine, or a combination thereof)can range from 1:1.2 to 1:50, inclusive thereof. In some embodiments,the ratio of glycopeptide antibiotic to N-acetyl-methionine (such asN-acetyl-D-methionine, N-acetyl-L-methionine, or a combination thereof)can be measured in relative weight components, and range from 1:1 to1:50, inclusive thereof.

The formulations and compositions disclosed herein can consist orconsist essentially of the listed ingredients. If the formulationsconsist essentially of the listed ingredients, other ingredients may bepresent so long as they do not affect the stability of the vancomycin inthe formulation, for example, as measured by assay.

Other suitable formulations for use in the present invention can befound in Remington's Pharmaceutical Sciences, Mace Publishing Company,Philadelphia, Pa., 17th ed. (1985).

Dosages

The concentration of glycopeptide antibiotic (such as vancomycin) or apharmaceutically acceptable salt in the formulation is about 1 mg/mL toabout 10 mg/mL and N-acetyl-methionine (such as N-acetyl-D-methionine,N-acetyl-L-methionine, or a combination) thereof in a concentration ofabout 1 mg/mL to about 5 mg/mL by weight.

The active compound is effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will be determined by a physician, in the light of therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered and itsrelative activity, the age, weight, and response of the individualpatient, the severity of the patient's symptoms, and the like.

Suitable doses are in the general range of from 0.01-100 mg/kg/day,preferably 0.1-50 mg/kg/day. For an average 70 kg human, this wouldamount to 0.7 mg to 7 g per day, or preferably 7 mg to 3.5 g per day. Insome embodiments, the preferred dosage is no less than 15 mg/kg/day.

Suitable doses and dosage regimens can be determined by range-findingtechniques which are a function of the subject's mass, body volume, bodysurface area, regions of administration, routes of administration, andthe degree of cancer prognosis of the subject. Generally, treatment isinitiated with smaller dosages that are less than the optimum dose ofthe composition of the present invention. Thereafter, the dosage isincreased by small increments until the optimum effect under thecircumstances is reached. The present method can involve theadministration of about 100 mg to about 3 grams total to the subject,preferably from about 500 mg to about 2 grams total to the subject.

To reduce the risk of infusion-related adverse reactions, theformulations and compositions of this disclosure when administeredintravenously (IV) to the subject or patient can be administered for atleast 60 minutes or more. In some embodiments, the formulations andcompositions can be administered by IV to the subject or patient at arate of 10 mg/min or less to reduce infusion-related adverse events.Other patient factors, such as age or obesity, may call for modificationof the usual intravenous daily dose.

In some embodiments, the injection concentration of the formulations andcompositions (such as a formulation or composition comprising vancomycinand N-acetyl methionine) can be about 1 mg/mL or less or about 5 mg/mLor less. In some embodiments, the injection concentration can be about 1mg/mL to about 5 mg/mL. In some embodiments, the injection concentrationcan be about 0.5 mg/mL, 1 mg/mL, about 2 mg/mL, 3 mg/mL, 4 mg/mL or 5mg/mL.

In some embodiments, the daily dose for an adult subject or patient is 2grams divided either as 500 mg every 6 hours or 1 g every 12 hours. Insome embodiments, the initial daily dose is at least about 15 mg/kg. Insome embodiments, the daily dose for a child is 10 mg/kg per dose every6 hours using a 500 mg vancomycin in 100 mL of solution, 750 mgvancomycin in 150 mL of solution, 1 gram vancomycin in 200 mL ofsolution, 1.25 gram vancomycin in 250 mL of solution, 1.5 gramvancomycin in 300 mL of solution, 1.75 gram vancomycin in 350 mL ofsolution, or 2 gram vancomycin in 400 mL of solution in a single-dosebag containing the formulations or compositions described herein.

Accordingly, this invention provides methods for treating infectiousdiseases, including those caused by Gram-positive organisms, in mammals.The compounds and compositions of this disclosure are particularlyuseful in treating infections caused by methicillin-resistantstaphylococci. Also, the compounds and compositions are useful intreating infection due to enterococci, including vancomycin-resistantenterococci (VRE). Examples of such diseases are severe staphylococcalinfections, for example, staphylococcal endocarditis and staphylococcalsepticemia. In some embodiments, the compounds and compositions of thisdisclosure are effective at treating coagulase negative staph. In someembodiments, the compounds and compositions of this disclosure areeffective at treating MRSA, enterocolitis, rheumatic fever,endocarditis, and/or colitis. The animal may be either susceptible to,or infected with, the microorganism. The method comprises administeringto the animal an amount of a compound of this invention, which iseffective for this purpose. In general, an effective amount of acompound of this invention is a dose between about 0.5 and about 100mg/kg. A preferred dose is from about 1 to about 60 mg/kg of activecompound. A typical daily dose for an adult human is from about 50 mg toabout 5 g.

In practicing this method, the antibiotic can be administered in asingle daily dose or in multiple doses per day. The treatment regimenmay require administration over extended periods of time, for example,for several days or for from one to six weeks. The amount peradministered dose or the total amount administered will depend on suchfactors as the nature and severity of the infection, the age and generalhealth of the patient, the tolerance of the patient to the antibioticand the microorganism or microorganisms in the infection.

In some embodiments, compositions comprising vancomycin of thisdisclosure can be administered systemically, such as by intravenous,intra-arterial or intraperitoneal administration, such that the finalcirculating concentration is from approximately 0.001 to approximately150 micromolar, or higher up to 200, 300, 400, 500, 600, 700, 800, 900or 1000 micromolar. The final circulating concentration can be 0.001,0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02,0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2., 0.3, 0.4, 0.5, 0.6,0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0,2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4,3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8,4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2,6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6,7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0,9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33,34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51,52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69,70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87,88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 100, 110, 120, 130,140, or 150 micromolar, or any concentration between any of the tworecited numbers, or higher as described above and any concentrationwithin the ranges noted. As mentioned herein, the invention alsocomprises combination therapies in which one or more additional activeagent is also administered to a subject. Skilled persons will appreciatedesirable dosages for the one or more active agent having regard to thenature of that agent and the principles discussed herein before.

In another embodiment, compositions comprising vancomycin may be used inthe invention alone or in combination with one or more additionalglycopeptides described herein in the use in the treatment of aparticular disorder. Co-administration may allow for improvedalleviation or amelioration of one or more symptoms, reduction of thelength or extent of a disease, delay or slowing of the progression ofdisease, amelioration, palliation or stabilisation of the disease state,partial or complete remission, prolonged survival and/or otherbeneficial therapeutic results. Such treatments may be administeredsimultaneously or sequentially in any order with a period of timebetween administrations. One of skill in the art will readily appreciatemethods of administering agents or therapies simultaneously orsequentially and possible time periods between administrations. Thetherapies may be administered by the same or different routes.

Manufacture and Stability

In some embodiments, the formulations and compositions of this inventionare substantially pure. By substantially pure is meant that theformulations comprise less than about 15%, about 10%, about 5%, or about1%, and preferably less than about 0.1%, of any impurity. In someembodiments, the total impurities, including metabolites of vancomycinand/or N-acetyl-methionine (such as N-acetyl-D-methionine,N-acetyl-L-methionine, or a combination thereof) will be not more thanabout 15%. In some embodiments, the total impurities will be not morethan about 12%. In some embodiments, the total impurities will be notmore than about 11%. In other embodiments, the total impurities will benot more than about 10%.

In some embodiments, the purity of the formulations and compositions ofthis invention may be measured using a method that includes, forexample, an ion exchange HPLC (AEX-HPLC), mass spectrometry, or acombination thereof. Mass spectrometry may include LC/MS or LC/MS/MS. Insome embodiments, the method used to measure the impurity may compriseboth AEX-HPLC and LC/MS.

Sterile compositions of this invention can be prepared using asepticprocessing by dissolving the compound in the formulation vehicle. In oneembodiment, the formulation may also be sterilized by filtration.Excipients used in the manufacture of the formulations of this inventionare widely used in pharmaceutical products and released to pharmacopeialstandards.

EXAMPLES Example 1: Example Vancomycin Hydrochloride InjectionComposition with N-Acetyl-D-Methionine

Table 1 below provides a listing of exemplary ingredients/componentssuitable for an exemplary formulation of the composition of theinvention and a desired weight/volume percentage for thoseingredients/components.

TABLE 1 Component Percentage No. Name of Ingredients (w/v) 1 VancomycinHydrochloride 0.1 to 1.0 2 N-Acetyl-Methionine 0.1 to 5.0 3 SodiumChloride 0.005 to 0.1  4 Hydrochloric acid QS* to adjust pH to about 4.5to about 5.5 5 Sodium Hydroxide QS to adjust pH to about 4.5 to about5.5 6 Water for Injection QS to 100% *QS = Quantum satis = Add as muchof the specified ingredient/composition as is needed to achieve thedesired result, but not more.

Example 2: Example Vancomycin Hydrochloride Injection Composition withN-Acetyl-D-Methionine

Table 2 below provides a list of ingredients/components of anotherrepresentative formulation of the invention.

TABLE 2 Component Percentage No. Name of Ingredients (w/v) 1 VancomycinHydrochloride 0.51 2 N-Acetyl-D-Methionine 2.5 (NADM) 3 Sodium Chloride0.01 4 Hydrochloric acid QS* to adjust pH to about 4.5 to about 5.5 5Sodium Hydroxide QS to adjust pH to about 4.5 to about 5.5 6 Water forInjection QS to 100% *QS = Quantum satis = Add as much of the specifiedingredient/composition as is needed to achieve the desired result, butnot more.

The formulation of Example 2 is made by the following steps:

-   -   1. In a suitable container, add 5.13 mg of vancomycin        hydrochloride to 800 mL of sterile water for injection;    -   2. Stir until the vancomycin hydrochloride is fully dissolved by        visual inspection;    -   3. Add 25 mg of N-acetyl-D-methionine (NADM) and stir until the        NADM is fully dissolved by visual inspection;    -   4. Add 120 mg of sodium chloride and stir until the sodium        chloride is fully dissolved by visual inspection;    -   5. Stir for additional 5 minutes;    -   6. Adjust the pH to 5.0, using 1.0 N Hydrochloric acid or sodium        hydroxide;    -   7. QS with water for injection to 1000 mL;    -   8. Stir for an additional 5 minutes; and    -   9. Aseptically fill the prepared solution into sterile bags of        appropriate size.

In some aspects, the order of solubilizing vancomycin (or apharmaceutically acceptable salt thereof (such as vancomycinhydrochloride)), sodium chloride (NaCl), and/or N-acetyl-D-methioninecan be performed in any order (i.e., first dissolve NaCl, then dissolvevancomycin or N-acetyl-D-methionine, then dissolve the remainingcomponent; or first dissolve vancomycin, then dissolve eitherN-acetyl-D-methionine or NaCl, then dissolve the remaining component).

In some aspects, the composition will have an osmolality. Osmolality isa measure of solubility of a solution (in wt.). In some aspects, thesolubility of the solution can be measured as per the osmolarity, whichis the molar solubility of a solution. In some aspects, the osmolalityof the compositions of this disclosure can range from about 100milliosmoles per kilogram (mOsm/kg) of solution to about 1000 mOsm/kg ofsolution. In some aspects, the osmolality of the composition can rangefrom about 275 mOsm/kg of solution to about 295 mOsm/kg of solution.

In some aspects, the composition will have a conductivity. Theconductivity of the aqueous composition can range from about 0.5 μS/cm(all conductivities are presented at 25° C.) to about 50 mS/cm. In someaspects, the conductivity of the solution can range from about 200 μS/cmto about 5 mS/com, inclusive thereof.

Example 3: Example Vancomycin Hydrochloride Injection Composition withN-Acetyl-D-Methionine

Table 3 below provides a list of ingredients/components of anotherrepresentative formulation of the invention.

TABLE 3 Component Percentage No. Name of Ingredient (w/v) 1 VancomycinHydrochloride 0.51 2 N-Acetyl-D-Methionine 1.5 3 Sodium Chloride 0.01 4Hydrochloric acid QS* to adjust to about pH 4.5 5 Sodium Hydroxide QS toadjust to about pH 4.5 6 Water for Injection QS to 100% *QS = Quantumsatis = Add as much of the specified ingredient/composition as is neededto achieve the desired result, but not more.

The formulation of Example 3 is made by the following steps:

-   -   1. In a suitable container, add 5.13 mg of vancomycin        hydrochloride to 800 mL of water for injection;    -   2. Stir till vancomycin hydrochloride is fully dissolved by        visual inspection;    -   3. Add 15 mg of N-acetyl-D-methionine (NADM) and stir until the        NADM is fully dissolved by visual inspection;    -   4. Add 120 mg of sodium chloride and stir until the sodium        chloride is fully dissolved by visual inspection;    -   5. Stir for additional 5 minutes;    -   6. Adjust the pH to 4.5, using 1.0N Hydrochloric acid or sodium        hydroxide;    -   7. QS with water for injection to 1000 mL;    -   8. Stir for additional 5 minutes; and    -   9. Aseptically fill the prepared solution into sterile bags of        appropriate size.

Example 4: Example Vancomycin Hydrochloride Injection Composition withN-Acetyl-D-Methionine

Additional embodiments of vancomycin HCl injection compositions withNADM and saline were prepared by the methods described above, with thefollowing compositions in Tables 4 & 5, respectively:

TABLE 4 Component Percentage No. Name of Ingredient (w/v) 1 VancomycinHydrochloride 0.51 2 N-Acetyl-D-Methionine (NADM) 2.0 3 Sodium Chloride0.2 4 Hydrochloric acid QS to adjust to about pH 4.5 to 5.5 5 SodiumHydroxide QS to adjust to about pH 4.5 to 5.5 6 Water for Injection QSto 100%

TABLE 5 Component Percentage No. Name of Ingredients (w/v) 1 VancomycinHydrochloride 0.51 2 N-Acetyl-D-Methionine (NADM) 2.5 3 Sodium Chloride0.1 4 Hydrochloric acid QS* to adjust to about pH 4.5 to about pH 5.5 5Sodium Hydroxide QS to adjust to about pH 4.5 to about pH 5.5 6 Waterfor Injection QS to 100%

Example 5: Stability Testing of Representative Formulations as Measuredin Glass Vials

The formulations prepared according to the invention as described in theabove examples were charged for stability under typical and/oraccelerated conditions to determine the effect of different factors suchas pH of the formulation, ratio of vancomycin to N-acetyl-D-methionineon the formulations. Also, simple vancomycin solutions were prepared inwater (where NO NADM was added) and adjusted to the indicated pH rangesand charged for stability. The stability condition includes 25° C./60%relative humidity. The solutions were stored in glass vials. Theanalytical results of the formulations at 25° C. are summarized in Table6 below.

TABLE 6 Ambient Condition (25° C./60% Relative Humidity (RH)) StabilityData in Glass Vials Vancomycin + Vancomycin + NADM NADM (25 VancomycinVancomycin Vancomycin Vancomycin (15 mg/mL) @ mg/mL) @ Time pH 3.0 pH4.0 pH 4.5 pH 5.0 pH 4.5 pH 4.5 Initial/0 103.3 103.1 104.8 103.6 95.2102 2 weeks 85.8 91.7 93.3 92.4 — —

As shown in Table 6 above, the results from the 3 months roomtemperature study experiment showed that the vancomycin solutions havingpH of about 4.5 and 5.0, prepared according to the methods describedherein, are stable formulations. The results demonstrate thatrepresentative formulations of the invention are at least stable asreference formulations.

Example 6: Stability Testing of Representative Formulations as Measuredin Glass Vials and Plastic Bags at Elevated Temperature

Formulations prepared as described herein were further studied at pH ofabout 4.5 to 5.0 in glass vial and plastic bag (PVC (polyvinyl chloride)or PP (polypropylene)) at room temperature (25° C.). The compositionswere introduced into vials or bags and then placed in stabilitychambers. At the appropriate time points, they were withdrawn andanalyzed for API assay by HPLC. The bags were PP BAGS FOR READY-TO-USESOLUTION from Technoflex, FR. A 6-month stability study was conductedand the observed results are set forth in Table 7.

TABLE 7 Vancomycin (5 mg/mL) Stability Data in Vials and Bags at 25°C./60% RH. Vancomycin Vancomycin HCl at pH HCl + 25 VancomycinVancomycin 4.5 in vials mg/mL HCl + 25 HCl + 25 (Control VancomycinHCl + 25 NAM at pH mg/mL mg/mL Formulation mg/mL NAM at pH 5.0 in PVCNAM at pH NAM at pH Without 5.0 in PP bags bags 5.0 in vials 4.5 invials Stabilizer) pH Assay pH Assay pH Assay pH Assay pH Assay 25° C.Initial/0 5.03 106.9 5.05 106.7 5.12 106.9 4.62 108 4.44 106.3 1 M 4.98106.2 4.98 106.6 4.98 105.4 4.51 102.1 4.94 81.9 3 M 4.99 107.1 5.03110.3 5.0 105.1 4.53 100.7 Precipitate 6 M 4.99 106.2 5.03 110 5.0 104.24.54 98.6 observed. Stability Discontinued

The results indicate that vancomycin-NAM compositions with a pH of 5.0are significantly more stable that the compositions at pH 4.5. Inaddition, all other conditions the same, the compositions were as stablein bags as they were in glass vials, indicating that any stability fromglass vials is equivalent to the same stability in bags.

There was a slight increase in the concentration of vancomycin in PVCbags relative to PP bags due to water loss, as bags are semi-permeablecontainers. Additionally, permeabilities of different materials will bedifferent.

Example 7: Pharmacokinetics Study

A subchronic IV/systemic study in a rat model is performed where theanimals are dosed via the tail vein daily for 28 days to determine thepotential for systemic toxicity. The rat was chosen as it has beensuccessfully used in other NADM non-clinical studies. A 28-day studyduration provides a conservative toxicological exposure period as perICH M3 (FDA/ICH. 2010. M3(R2) Nonclinical Safety Studies for the Conductof Human Clinical Trials and Marketing Authorization for Pharmaceuticals(FDA 2010)).

The study cohorts (M—male, F—female) are shown below in Table 8.Parameters to evaluate include morbidity/mortality, clinicalobservations, body weight, food consumption, ophthalmology, hematology,clinical chemistry, urinalysis (including water intake and analysis forNADM and metabolites), organ weight, gross pathology, andhistopathology. In addition, toxicokinetic (TK) analyses are performedon samples collected on study days 1 and 28. The TK samples will provideinformation on systemic exposure and parameters, such as the maximumserum concentration that a drug achieves in a tested area or a specifiedcompartment after the drug has been administered and before theadministration of a second dose (Cmax) and the amount of time that adrug is present at the maximum concentration in serum (Tmax). Themaximum daily dose (MDD) for humans for NADM is about 0.17 g/kg/day (10g/day for 60 kg person=0.167 g/kg/day), which translates to a ratequivalent dose of about 1.05 g/kg/day (FDA. 2005a. Guidance forIndustry Estimating the Maximum Safe Starting Dose in Initial ClinicalTrials for Therapeutics in Adult Healthy Volunteers. Center for DrugEvaluation and Research (CDER). July 2005 (FDA 2005a); calculated bydividing the human MDD by the rat-to-human conversion factor of 0.16).The high dose in this rat study therefore should be at least about 3.15grams NADM/kg/day to allow for an about 3× margin of safety over thehuman equivalent maximum clinical dose. Without undue burden, theexperiment can be performed on a range of dosages as described herein.

TABLE 8 Main Study - # TK Study - # Group Dose (mg/kg/day) animalsanimals Control (product 0 10 M/10 F (20) 3 M/3 F (6) solution withoutimpurities or API) Low NADM TBD 10 M/10 F (20) none Mid NADM TBD 10 M/10F (20) 3 M/3 F (6) High NADM TBD 10 M/10 F (20) 3 M/3 F (6)

Example 8. Demonstration of Antibacterial Activity of RepresentativeCompositions of the Invention

In Vitro

First, the minimal inhibitory concentration (MICs) of the vancomycin inthe compositions of this disclosure are determined.

Bacterial strains from either American Type Tissue Culture Collection(ATCC) or the Centers for Disease Control (CDC), or the Mayo Clinic areobtained and used as described herein.

Minimal inhibitory concentrations (MICs) are measured in a microdilutionbroth procedure under NCCLS (National Committee for Clinical LaboratoryStandards) guidelines (Ginocchio, C., “Role of NCCLS in antimicrobialsusceptibility testing and monitoring,” Am. J. Health Syst. Pharm., 2002Apr. 15; 59(8 Suppl 3):57-11. doi: 10.1093/ajhp/59.suppl_3.S7. Thecompositions are serially diluted into Mueller-Hinton broth in 96-wellmicrotiter plates. Overnight cultures of bacterial strains are dilutedbased on absorbance at 600 nm so that the final concentration in eachwell was 5×106 cfu/mL. At a selected timepoint, MICs are determined byvisual inspection of the plates Strains routinely tested in the initialscreen included methicillin-sensitive Staphylococcus aureus (MSSA),methicillin-resistant Staphylococcus aureus, methicillin-sensitiveStaphylococcus epidermidis (MSSE), methicillin-resistant Staphylococcusepidermidis (MRSE), vancomycin sensitive Enterococcus faecium (VSE Fm),vancomycin sensitive Enterococcus faecalis (VSE Fs), vancomycinresistant Enterococcus faecium also resistant to teicoplanin (VRE Fm VanA), vancomycin resistant Enterococcus faecium sensitive to teicoplanin(VRE Fm Van B), vancomycin resistant Enterococcus faecalis alsoresistant to teicoplanin (VRE Fs Van A), vancomycin resistantEnterococcus faecalis sensitive to teicoplanin (VRE Fs Van B),enterococcus gallinarium of the Van A genotype (VRE Gm Van A),enterococcus gallinarium of the Van C-1 genotype (VRE Gm Van C-1),enterococcus casseliflavus of the Van C-2 genotype (VRE Cs Van C-2),enterococcus flavescens of the Van C-2 genotype (VRE Fv Van C-2), andpenicillin-sensitive Streptococcus pneumoniae (PSSP) andpenicillin-resistant Streptococcus pneumoniae (PSRP). Compositions whichhave significant activity against the strains set forth above are thentested for MIC values in a larger panel of clinical isolates includingthe species listed above and non-speciated coagulase negativeStaphylococcus both sensitive and resistant to methicillin (MS-CNS andMR-CNS). Those compositions are also were tested for MICs against gramnegative organisms, such as Escherichia coli and Pseudomonas aeruginosa.

The vancomycin-comprising compositions of this invention are expected tobe active in the above in vitro test and demonstrate a broad spectrum ofactivity.

In Vivo Determination of Antibacterial Activity

Tolerability Studies in Mice

A vancomycin-comprising composition as described herein is administeredeither intravenously or subcutaneously to a first cohort of mice andobserved for 5-15 minutes. The dose is increased to a second cohort ofmice upon the observation of no adverse effects in the first cohort. Thedose incrementation is to be continued until mortality occurred, or thedose is maximized. Dosing begins at 15 mg/kg and increases until themaximum tolerated dose (MTD) is achieved.

Mouse Septicemia Model

An appropriately virulent strain of bacteria (most commonly S. aureus,or E. Faecalis or E. Faecium) is administered to mice (N=10 mice pergroup) intraperitoneally. The bacteria is combined with hog gastricmucin to enhance virulence. The dose of bacteria (normally 10{circumflexover ( )}6-10{circumflex over ( )}7 bacterial particles) is sufficientto induce mortality in all of the mice over a three day period. One hourafter the bacteria is administered, a vancomycin-comprising compositionas described herein is administered in a single dose either IV orsubcutaneously. Each dose is administered to groups of 10 mice, at dosesthat range from a maximum of about 15 mg/kg to a minimum of less than 1mg/kg. A positive control (normally vancomycin with vancomycin sensitivestrains) is administered in each experiment. The (EC50) dose at whichapproximately 50% of the animals are saved is calculated from theresults.

Neutropenic Thigh Model

An appropriately virulent strain of bacteria (most commonly S. aureus,or E. Faecalis or E. Faecium, sensitive or resistant to vancomycin) isadministered to a first cohort of mice. Mice are initially renderedneutropenic by administration of cyclophosphamide at 200 mg/kg on day 0and day 2. On day 4 they are infected in the left anterior thigh by anIM injection of a single dose of bacteria. The mice are thenadministered a vancomycin-comprising composition of this disclosure at aselected time (e.g., one hour) after the bacteria and at various otherselected time s (e.g., 1, 2, 4 and 24 hours) the mice are sacrificed(minimum of 3 per time point) the thigh excised, homogenized and thenumber of CFUs (colony forming units) are determined by plating. Bloodis also plated to determine the CFUs in the blood.

The vancomycin-comprising compositions of this invention are expected tobe active in the above in vivo test and demonstrate a broad spectrum ofactivity.

It will be understood that the foregoing description is of exemplaryembodiments of this invention, and that the invention is not limited tothe specific forms shown. Modifications may be made in the design andarrangement of the elements without departing from the scope of theinvention.

The invention described and claimed herein have many attributes andembodiments including, but not limited to, those set forth or describedor referenced in this Detailed Description. It is not intended to beall-inclusive and the inventions described and claimed herein are notlimited to or by the features or embodiments identified in this DetailedDescription, which is included for purposes of illustration only and notrestriction. A person having ordinary skill in the art will readilyrecognize that many of the components and parameters may be varied ormodified to a certain extent or substituted for known equivalentswithout departing from the scope of the invention. It should beappreciated that such modifications and equivalents are hereinincorporated as if individually set forth. The invention also includesall of the steps, features, compositions and compounds referred to orindicated in this specification, individually or collectively, and anyand all combinations of any two or more of said steps or features.

All patents, publications, scientific articles, web sites, and otherdocuments and materials referenced or mentioned herein are indicative ofthe levels of skill of those skilled in the art to which the inventionpertains, and each such referenced document and material is herebyincorporated by reference to the same extent as if it had beenincorporated by reference in its entirety individually or set forthherein in its entirety. Applicants reserve the right to physicallyincorporate into this specification any and all materials andinformation from any such patents, publications, scientific articles,web sites, electronically available information, and other referencedmaterials or documents. Reference to any applications, patents andpublications in this specification is not, and should not be taken as,an acknowledgment or any form of suggestion that they constitute validprior art or form part of the common general knowledge in any country inthe world.

The specific methods and compositions described herein arerepresentative of preferred embodiments and are exemplary and notintended as limitations on the scope of the invention. Other objects,embodiments, and embodiments will occur to those skilled in the art uponconsideration of this specification, and are encompassed within thespirit of the invention as defined by the scope of the claims. It willbe readily apparent to one skilled in the art that varying substitutionsand modifications may be made to the invention disclosed herein withoutdeparting from the scope and spirit of the invention. The inventionillustratively described herein suitably may be practiced in the absenceof any element or elements, or limitation or limitations, which is notspecifically disclosed herein as essential. Thus, for example, in eachinstance herein, in embodiments or examples of this, any of the terms“comprising”, “consisting essentially of”, and “consisting of” may bereplaced with either of the other two terms in the specification. Also,the terms “comprising”, “including”, containing”, etc. are to be readexpansively and without limitation. The methods and processesillustratively described herein suitably may be practiced in differingorders of steps, and that they are not necessarily restricted to theorders of steps indicated herein or in the claims. It is also that asused herein and in the appended claims, the singular forms “a,” “an,”and “the” include plural reference unless the context clearly dictatesotherwise. Under no circumstances may the patent be interpreted to belimited to the specific examples or embodiments or methods specificallydisclosed herein. Under no circumstances may the patent be interpretedto be limited by any statement made by any Examiner or any otherofficial or employee of the Patent and Trademark Office unless suchstatement is specifically and without qualification or reservationexpressly adopted in a responsive writing by Applicants. Furthermore,titles, headings, or the like are provided to enhance the reader'scomprehension of this document, and should not be read as limiting thescope of this. Any examples of embodiments, embodiments or components ofthe invention referred to herein are to be considered non-limiting.

The terms and expressions that have been employed are used as terms ofdescription and not of limitation, and there is no intent in the use ofsuch terms and expressions to exclude any equivalent of the featuresshown and described or portions thereof, but it is recognized thatvarious modifications are possible within the scope of the invention asclaimed. Thus, it will be understood that although this has beenspecifically disclosed by preferred embodiments and optional features,modification and variation of the concepts herein disclosed may beresorted to by those skilled in the art, and that such modifications andvariations are considered to be within the scope of this invention asdefined by the appended claims.

The invention has been described broadly and generically herein. Each ofthe narrower species and subgeneric groupings falling within the genericdisclosure also form part of the invention. This includes the genericdescription of the invention with a proviso or negative limitationremoving any patient matter from the genus, regardless of whether or notthe excised material is specifically recited herein.

Other embodiments are within the following claims. In addition, wherefeatures or embodiments of the invention are described in terms ofMarkush groups, those skilled in the art will recognize that theinvention is also thereby described in terms of any individual member orsubgroup of members of the Markush group.

What is claimed is:
 1. A liquid composition comprising: (a) one or moreglycopeptide antibiotics or a pharmaceutically acceptable salt thereofin an amount of about 0.1% by weight to about 1.0% by weight, (b)N-acetyl-methionine in an amount of about 0.1% by weight to about 5.0%by weight, and (c) one or more pharmaceutically acceptable excipients.2. The liquid composition of claim 1, wherein the one or moreglycopeptide antibiotics or the pharmaceutically acceptable salt thereofis vancomycin or vancomycin hydrochloride.
 3. The liquid composition ofclaim 2, wherein the concentration of vancomycin or vancomycinhydrochloride is about 5.0 mg/mL.
 4. The liquid composition of claim 1,wherein the N-acetyl-methionine is N-acetyl-D-methionine,N-acetyl-L-methionine, or a combination thereof.
 5. The liquidcomposition of claim 4, wherein the concentration ofN-acetyl-D-methionine is about 15 mg/mL to about 25 mg/mL.
 6. The liquidcomposition of claim 1, wherein the one or more glycopeptide antibioticsor the pharmaceutically acceptable salt thereof is vancomycinhydrochloride, wherein the N-acetyl-methionine is N-acetyl-D-methionine,and wherein the weight ratio of vancomycin hydrochloride toN-acetyl-D-methionine present in the liquid composition is about 1:3 byweight to about 1:5 by weight, about 1:1 by weight to about 1:100 byweight, 1:1 by weight to about 1:50 by weight, or 1:1 by weight to 1:10by weight.
 7. The liquid composition of claim 1, wherein the liquidcomposition does not include N-acetyl D-alanine, polyethyleneglycol-400, or both N-acetyl D-alanine and polyethylene glycol-400. 8.The liquid composition of claim 1, wherein the liquid composition is anaqueous solution.
 9. The liquid composition of claim 1, wherein theliquid composition has a pH of about 2 to about 7, or about 5.0 adjustedwith one or more hydrochloric acid solution or sodium hydroxide.
 10. Theliquid composition of claim 1, wherein the liquid composition is aready-to-use solution for intravenous, subcutaneous or intramuscularadministration to a subject.
 11. The liquid composition of claim 1,wherein the one or more pharmaceutically acceptable excipients is one ormore buffers, one or more buffering agents, one or more chelating agent,one or more tonicity agents, one or more pH adjusting agents, one ormore antioxidants, one or more preservatives, water, or a combinationthereof.
 12. A liquid composition comprising: (a) vancomycinhydrochloride in an amount of about 0.5% by weight, (b)N-acetyl-methionine in an amount of about 1.5% to about 2.5% by weight,(c) sodium chloride in an amount of about 0.012% by weight, (d) sodiumhydroxide or hydrochloride to adjust the composition pH of about 5.0,and (e) water.
 13. The liquid composition of claim 12, wherein theN-acetyl-methionine is N-acetyl-D-methionine, N-acetyl-L-methionine, ora combination thereof.
 14. The liquid composition of claim 1, whereinthe liquid composition is a solution filled in a vial, an ampoule, abag, a bottle, a cartridge, or a syringe.
 15. The liquid composition ofclaim 11, wherein the one or more tonicity agents is sodium chloride.16. The liquid composition of claim 1, wherein the liquid compositionfurther comprises about 2.5% or less of total impurities.
 17. The liquidcomposition of claim 1, wherein the liquid composition is stable for atleast 3 months at 25±2° C.
 18. The liquid composition of claim 1,wherein the one or more glycopeptide antibiotics or the pharmaceuticallyacceptable salt thereof is vancomycin, teicoplanin, ramoplanin,complestatin, corbomycin, bleomycin, oritavancin, dalbavancin,telavancin, or a combination thereof.
 19. A liquid compositioncomprising: (a) one or more glycopeptide antibiotics or apharmaceutically acceptable salt thereof, and (b) N-acetyl-methionine;wherein the molar ratio of the one or more glycopeptide antibiotics orthe pharmaceutically acceptable salt thereof to the N-acetyl-methioninepresent in the liquid composition is about 1:5 by molar to about 1:50 bymolar.
 20. The liquid composition of claim 19, wherein the one or moreglycopeptide antibiotics or the pharmaceutically acceptable salt thereofis vancomycin or vancomycin hydrochloride.
 21. The liquid composition ofclaim 19, wherein the N-acetyl-methionine is N-acetyl-D-methionine,N-acetyl-L-methionine, or a combination thereof.
 22. The liquidcomposition of claim 19, wherein the one or more glycopeptideantibiotics or the pharmaceutically acceptable salt thereof isvancomycin, teicoplanin, ramoplanin, complestatin, corbomycin,bleomycin, oritavancin, dalbavancin, telavancin, or a combinationthereof.